Whereas, most patients with acute pancreatitis recover completely following conventional treatment, a significant number develop serious or lethal complications, such as respiratory insufficiency. Active proteolytic enzymes may not only be confined to the gland parenchyma during episodes of acute pancreatitis, but also may gain access to the circulation or to the lymphatic system and mediate tissue damage in organs which are quite remote from the original focus of inflammation and necrosis. Injury may be mediated either directly by free enzymes or indirectly by effects of such enzymes on the coagulation, fibrinolytic, complement, or kinin cascades. The possibility exists, therefore, that during episodes of acute pancreatitis, a sufficient imbalance between active proteases and antiproteases may occur and lead to the generation in the circulation of humoral mediators of inflammation and tissue injury. In fact, we and others have found evidence of complement catabolism in some patients with acute pancreatitis. The objective of the proposed research is to examine in detail in animals with experimental pancreatitis and in patients with acute alcoholic pancreatitis, mechanisms and consequences of complement activation. Experiments have been designed to test the following hypotheses: (1) Complement activation occurs during the course of acute pancreatitis as a consequence of protease-antiprotease imbalance. (2) Proteolytic cleavage of native complement components leads to the formation of biologically-active peptides (e.g., C5a) capable of provoking lung injury. (3) The extent of complement activation reflects the severity of pancreatic inflammation (necrosis) and correlates with the development of extrapancreatic organ involvement (i.e., respiratory insufficiency). (4) Measurements of complement components are of value for identifying high risk patients with acute pancreatitis.